Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study

Abstract

BackgroundObesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline.MethodsC57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 – 10 subjects per group per time point, 100 total; 4 – 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons.ResultsReductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits.ConclusionsDifferences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s12968-015-0180-7) contains supplementary material, which is available to authorized users.

Cardiovascular magnetic resonance detects the progression of impaired myocardial perfusion reserve and increased left-ventricular mass in mice fed a high-fat diet

“…Coronary arterioles from HFD mice also had a reduced response to acetylcholine, showing endothelial dysfunction as well as impaired passive tone in response to increasing pressure steps. The finding that impaired MPR occurs after 18 weeks of HFD is consistent with the recently-established time course for impaired systolic strain with dobutamine stress, which occurred at 22 weeks of HFD but not 16 weeks [30]. Furthermore, we showed that 18 weeks of HFD in mice resulted in increased LV mass and increased LVWT without changes in LV volumes and peak LV E cc .…”

Of mice (dogs) and men: getting to the heart of obesity-associated cardiac dysfunction

“…These models have generally been found to recapitulate common findings from human obesity, such as LV hypertrophy, systolic dysfunction [7, 15,16, 17] and restricted coronary flow reserve [18]. Collectively, we have gained valuable insights from these studies, such as the mechanistic relationship between insulin resistance and cardiac remodelling/dysfunction [6, 15, 19].…”

“…It is instinctive, and easy given the direct compatibility of MRI measurements between animals and humans, to directly extrapolate from studies like that of Broussard et al [21] and others [16, 17] to human disease, but such an exercise is fraught with challenges. For example, while reduced cardiac mechanics in animals are generally consistent with findings in human studies, the details of reduced circumferential strain and torsion are subject to debate, as some human studies have found no change [12] or even increases [13] in those specific measures.…”

“…In addition, it is difficult to predict the extent to which the processes governing an acute response to a high-fat diet in animals are similar to and representative of the processes governing a chronic response to obesity in humans. In fact, mice fed a high-fat diet may have an acute increase in myocardial strain and torsion after 4–10 weeks [16], suggesting that there may in fact be inter-species differences in these responses. Furthermore, while cardiac dysfunction can occur independently of cardiac remodelling or arterial hypertension, it cannot be stated that cardiac dysfunction in humans is in fact free of such interactions, because these factors are often present and will affect function.…”

Review of Journal of Cardiovascular Magnetic Resonance 2015

“…Haggerty et al evaluated LV mechanics under both resting and stress conditions in a murine obesity model to investigate whether or not LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline [184]. Cine displacement encoding with stimulated echoes (DENSE) with a temporal resolution of 7.4 ms was applied at rest (baseline) and at pharmacologically induced stress longitudinally over a period of 55 weeks.…”